1. Field of the Invention
The present invention relates to a novel anti-cancer drug delivery system, wherein a somatostatin analog is conjugated with an anticancer drug, such as paclitaxel, so that the anticancer drug can be delivered specifically to the targeted cancer cells.
2. Description of the Related Art
Most cytotoxic anticancer drugs suffer from a common problem, i.e. toxic side effects due to the lack of a selective drug delivery system. Using endocytotic ligands as carriers of the anticancer drugs to target these drugs to the cancer cells can avoid or reduce toxic side-effects and greatly improve the efficiency of these drugs"" delivery.
Somatostatins function through cellular membrane receptors, known as somatostatin receptors (SSTR). These receptors are over expressed on the surfaces of certain tumor cells, such as carcinoid, islet cell of the pancreas, paragangliomas and small-cell carcinomas of lungs. Since somatostatin analogs possess such interesting properties, they may be used as a carrier system targeted to those malignant tumor cells such that the drugs can specifically act on those cells. It has been reported that somatostatin analogs including X-c[Cys-Phe-Trp-Lys-Thr-Cys]-X, X-c[-Cys-Tyr-D-Trp-Lys-Val-]-X, or X-c[Cys-Phe-D-Trp-Lys-Thr-Cys]-X are labeled with chromatic or radionuclide to visualize and monitor the tumors that express SSTRs. Somatostatin analogs are particularly preferred for these applications to the original somatostatins because such analogs are known to be smaller in size, higher in affinities to the somatostatin receptors, and more metabolism stable than the original somatostatins.
The present invention is directed to a combination of somatostatin analogs, such as octreotide, lanreotide, and vapreotide, and a cytotoxic drug, such as paclitaxel, through a covalent bond or a physical encapsulation. The inventive compound of the present invention has the following general structure:
X-spacer-NH-peptide
wherein X is an anticancer drug, a lipid for making a liposome, or a monomer for forming a polymer matrix.
In general, this invention employs somatostatin analogs having sequence of X-c[Cys-Phe-Trp-Lys-Thr-Cys]-X, X-c[-Cys-Tyr-D-Trp-Lys-Val-]-X, or X-c[Cys-Phe-D-Trp-Lys-Thr-Cys]-X to provide a new system for delivering anti-cancer drugs to the cancer cells. The synthesis of somatostatin analogs is preferably performed on a solid-phase peptide synthesizer using Fmoc chemistry. The desired compound, such as anticancer drugs paclitaxel, doxorubicin or camptothecin or the like, that is intended to be delivered to the target cells, reacts with a spacer (preferably having a carboxyl terminal group) to form a covalent bond, resulting in a drug-spacer complex. Such complex is then coupled to the N-terminal of the somatostatin analog peptide on the resin to form the final product, namely, a drug-spacer-peptide complex, as shown in FIG. 1. The present invention further provides a method of synthesizing a DOPE-PEG-spacer-somatostatin analog complex, which is useful for the preparation of a liposome drug delivery system, as shown in FIG. 1.
The various features of novelty that characterize the invention are pointed out with particularity in the claims annexed to and forming a part of the disclosure. For a better understanding of the invention, its operating advantages, and specific objects attained by its use, reference should be had to the drawing and descriptive matter in which there are illustrated and described preferred embodiments of the invention.